Etoposide and teniposide are 4'-demethylepipodophyllotoxin glucoside derivatives which are widely used in clinical therapy for treating cancer. In particular, etoposide is approved in the United States for treating small cell lung cancer and testicular cancer. However, etoposide exhibits limited solubility in water which makes it difficult to formulate into suitable pharmaceutical compositions.
To increase the water solubility of etoposide and its ability to be administered, etoposide phosphate is prepared as a prodrug. Etoposide phosphate metabolizes within the body to etoposide which can then be utilized by the body. One example of a water soluble prodrug is described in U.S. Pat. No. 4,904,768 which discloses water soluble prodrugs of 4'-demethylepipodophyllotoxin glucoside derivatives bearing a 4'-phosphate group. One example disclosed therein is etoposide 4'-phosphate. Etoposide 4'-phosphate is prepared by reacting etoposide with phosphorous oxychloride followed by hydrolysis, or by reacting etoposide with diphenyl chlorophosphate followed by hydrogenation to remove the phenyl groups.
The preparation of epipodophyllotoxin glycosides are also disclosed in U.S. Pat. No. 4,997,931. The 4'-demethylepipodophyllotoxin glycosides are prepared by condensing 4'-protected 4'-demethylepipodophyllotoxin with a protected sugar. The resulting compound is then derivatized to produce the corresponding 4'-phosphate.
The previous processes for preparing etoposide and etoposide phosphate typically require the protection of the phenol, coupling with a protected sugar and then the removal of the protecting groups. In addition, most of these methods require different protecting groups for the hydroxy and phosphate groups. The different protecting groups require multiple steps to remove respective protecting groups. The deprotection steps often require acid or alkaline conditions, which can degrade the final product, resulting in low yields.
Etoposide phosphate is usually prepared from etoposide by the additional steps of phosphorylation and deprotection. These multiple steps typically result in lower overall yields of the desired compounds as well as the expense and difficulty of producing the compounds due to undesirable phosphorylation of the glucosidic hydroxyls on etoposide.